The mitogen activated protein (MAP) kinase family member c-jun-N-terminal kinase (JNK) has been shown to be a compelling therapeutic target for a variety of diseases including neurodegeneration, metabolic disorders, inflammation, cardiovascular disease, and cancer. Validation for JNK as a therapeutic target has come from studies employing knock out (KO) mice, peptide inhibitors of JNK and small molecule ATP competitive inhibitors of JNK. The case for JNK as a therapeutic target for cardiovascular disease, and in particular myocardial infarction (MI), is very compelling due to the fact that mitochondrial dysfunction contributes significantly to this disease and JNK is a crucial mediator of cell death signaling via its association with mitochondria in cardiomyocytes both in vitro and in vivo. Indeed, many studies have linked activation of the JNK mitochondrial pathway to cardiomyocyte cell death. For example, it has been shown that jnk1−/− or jnk2−/−, or transgenic mice expressing dominant negative JNK1/2, showed less injury and cellular apoptosis following I/R injury in vivo. The activation of JNK in rabbits subjected to coronary artery ligation followed by reperfusion in vivo as well as in vitro in isolated adult rabbit cardiomyocytes has also been demonstrated. In the latter case, virally expressed dominant negative JNK2 or JNK-interacting protein-1 (JIP) (a 154-amino acid protein substrate competitive inhibitor of JNK) were shown to be protective against simulated I/R in these cell. It has been shown that inhibition of JNK by AS601245 (an ATP competitive inhibitor) decreased cardiomyocyte apoptosis and infarct size in rats after I/R suggesting a therapeutic benefit for JNK inhibition. Since that time, numerous other reports have shown a clear correlation between JNK translocation to the mitochondria and cardiomyocyte death in response to simulated ischemia. For example, primary adult rat cardiomyocytes have been utilized to demonstrate that JNK was activated by oxidative stress and localized to the mitochondria in response to this stress. It has also been shown that inhibiting JNK activation or JNK translocation to the mitochondria with a specific peptide that inhibits JNK-Sab interaction prevents ROS generation, mitochondrial membrane potential dissipation, and cell death.
LRRK2 is a member of the leucine-rich repeat kinase family, and variants of the PARK8 gene which encodes for the enzyme are associated with an increased risk of Parkinsion's disease and Crohn's disease. The Gly2019Ser mutation is one of a small number of LRRK2 mutations proven to cause Parkinson's disease.
The design and identification of potent and highly selective JNK and LRRK2 inhibitors has been pursued in the past few years due to potential wide spread therapeutic applications. In particular, development of brain penetrant small molecule inhibitors for JNK and LRRK2 has been a major focus in order to develop efficacious therapeutics for Parkinson's disease (PD) and other neurodegenerative diseases, such as Alzheimer's (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). Additionally, inhibition of JNK and/or LRRK2 is believed to be an effective approach for development of therapeutic compounds for treatment of myocardial infarction (MI), obesity, diabetes, Alzheimer's disease, ALS, cancer, rheumatoid arthritis, fibrotic disease, pulmonary fibrosis, kidney disease, liver inflammation, and Crohn's disease.